IDSA

T-20. At the recent IDSA meeting, preliminary data was reported from
a phase I/II dose escalating study of T-20. T-20 inhibits fusion of HIV with
host cells (CD4s). Although the following data is encouraging, it is preliminary
and is from early stages of research in humans. Further studies are needed to
evaluate T-20's efficacy and safety. Fusion inhibition's approach to HIV therapy
is different than any other currently approved HIV antiviral.

16 treatment-naive or experienced (off drugs for 15 days prior to starting
T-20) individuals received doses of 3, 10, 30 or 100 mg of T-20 every 12 hours
for 14 days.

Follow-up studies are necessary to confirm preliminary findings. Sub-cutaneous
administration is expected to be explored in a forthcoming study.

Nelfinavir: 12 month data report

This is a brief preliminary report of the important information reported in
this abstract. A more extensive report will follow. This report contains the
data out to 12 months for participants in nelfinavir study #511 which compared
750 mg nelfinavir three times per day plus AZT/3TC, 500 mg nelfinavir 3X/day
plus AZT/3TC and AZT/3TC alone.

The 750 mg 3x/day dose regimen of nelfinavir is the only one approved by the
FDA and in fact produced superior results in this study to the 500 mg dose.

297 individuals were randomized to one of the 3 arms. About 100 were randomized
to the nelfinavir 750 mg 3x/day regimen. The participants were treatment naive.
Their baseline CD4 and viral load were 283 cells and 4.83 log (about 67,000
copies/ml), respectively. After 12 months the viral load reduction for this
arm was about 2 log, 80% were undetectable (<500 copies/ml), and CD4 increases
were about 170 cells from baseline.

The investigators did some additional research relevant to the current treatment
environment. The higher a participant's CD4 was at baseline the higher the likelihood
to reach undetectable and sustain it. For those with >300 CD4 at baseline,
83% were undetectable. The lower a person's viral load was at baseline the more
likely they would be successful with treatment. For participants whose baseline
viral load was <50,000 copies/ml, 95% were undetectable at 12 months. This
scores a point in favor of early aggressive treatment for HIV.

DMP-266

48 week efficacy data was reported for participants in this study which compared
two arms. One group received DMP-266, a new NNRTI from DuPont Merck, plus indinavir
in a two drug combination. The other group received indinavir monotherapy. After
12 weeks those taking indinavir monotherapy were permitted to add d4T+DMP-266.

The baseline viral load and CD4 was about 5 log (100,000 copies/ml) and 283
cells. 71% of the participants had some level of prior NRTI experience but were
protease inhibitor and NNRTI naive.

After 48 weeks (n-47), the individuals in the DMP-266+indinavir arm had a reduction
in HIV RNA from baseline of about 2.4 log, 88% were undetectable (<400 copies/ml),
and their increase in CD4 was +245 from baseline. After 48 weeks (n=31), the
individuals who were in the other group had a reduction in viral load of 1.89
log, 68% were undetectable, and had a CD4 increase of +150 cells.

There were 11 premature discontinuations in the DMP-266/indinavir arm and 9
in the other arm.

Tolerability - Rash Summary

Toxicity Grade

DMP-266+indinavir

Indinavir

I

19/84 (22.6%)

11/42 (26.2)

II

9/84 (10.7%)

1/42 (2.4%)

III

0/84

1/42

IV

28/84 (33.3%)

13/42 (31%)

1st Report of Highlights From ICAAC

Tuesday, 1997, Toronto, Canada.

This is an initial report of important treatment highlights from the 37th annual
ICAAC conference in Toronto.

At the opening session Sunday evening, Dr Robert Siliciano of Johns Hopkins
University discussed his findings of a viral reservoir of post integrated proviral
DNA persisting in resting CD4 memory t-cells. These cells are in a reversible
state of non-productive infection but can be capable of producing infectious
virus if stimulated by antigen. He said that the frequency of these cells and
their decay rate are important to evaluating the effect on the potential for
eradication.

Using a sensitive assay he found the frequency of these cells to be extremely
low. The replication competent integrated proviral DNA was found in <.01%
of resting CD4+ t-cells. He took a lymph node biopsy of 14 individuals from
the Ho studies and found significantly that the frequency of these cells are
not different in the blood and the lymph node. This is important because it
allows researchers to access this compartment just by taking a peripheral blood
sample. He ran an independent assay, a virus culture, because there was thinking
that all the DNA was not competent to reproduce virus. His findings were confirmed.

In order to determine the decay rate of these cells Siliciano entered into
a collaboration with clinical researchers to see if this reservoir persists
in individuals who have been on long term highly active antiretroviral therapy
(HAART). For this study, he selected patients who were likely to maintain a
high level of compliance to the regimens; who were on three or four drugs at
least one of which was a protease inhibitor; who had a rapid response to therapy
(who became undetectable within 2-3 months); and, who remained undetectable
(200 copies/ml) with multiple measurements for the period of study including
the times for which they took blood to look for latently infected cells.

Replication competent proviral DNA was found in resting CD4+ t-cells in essentially
all the individuals (18/18), including those who were on therapy for up to 30
months, and it can persist for a while. In four patients they were unable to
get enough resting CD4 t-cells to conduct proper tests. Unfortunately, he concluded
that the frequency of these cells in the study individuals was not reduced by
being on therapy for a longer period of time. The frequency for those who were
on therapy the longest was not much different for those individuals who were
on therapy for a short period of time. He said we will have to conduct studies
following individuals over time to try and determine the decay rates of these
cells.

For comparison sake, it has been generally accepted that free virus only persists
for minutes or hours. Cells that produce most of the virus last only a day or
two. Cells with unintegrated DNA retain the ability to produce virus for only
a few days. Extracellular virus particles bound to follicular dendritic cells
(in the lymph tissue) last for about two weeks. Although we have less information
on chronically infected macrophages, their half-life appears to be about two
weeks. The half-life of resting CD4+ t-cells with integrated proviral DNA could
be a 5 to 7 months. This is consistent with the fact that these are memory t-cells
and their biological function is to persist. Some researchers have said to me
that memory cells can last for a number of years.

After being on HAART for a period of time, an individual may experience a partial
restoration of the immune system. If the CD4 cells increase appreciably in conjunction
with some immune restoration it is possible that the immune system could control
any virus that could be produced by the activation of these resting cells. This
can only be determined by following individuals over time.

David Ho and the ACTG are planning to conduct studies of strategies designed
to target these cells. Stay tuned.

Dr Charles Farthing of the AIDS Healthcare Foundation in Los Angeles presented
this report. 13 individuals were selected from the study# 462 (ritonavir+saquinavir)
to participate in this substudy. These were individuals with undetectable HIV
RNA (<200 copies) for at least 8 weeks after one year of therapy. None of
these individuals added RTIs, they were only receiving ritonavir+saquinavir.
Their baseline CD4 and viral load were about 50,000 copies/ml and 234 CD4. 6/13
were taking 400 mg bid of both drugs. However, there was no baseline CSF viral
load measurement, so there was no basis for comparison, and they did not measure
for CSF levels of ritonavir or saquinavir. Still, the following results are
encouraging but need to be followed with additional studies better designed
to form more definitive conclusions. Abbott said such a study is in progress.

In this substudy 12/13 had CSF viral load <400 copies/ml. One patient on
ritonavir+saquinavir had plasma viral load <200 copies/ml but had a CSF viral
load equal to 650 copies/ml.

This was reported at the IDSA meeting earlier in September but I thought it
would fit nicely here. Dr Anne Collier of the University of Washington reported
this information. She found indinavir drug levels in the CSF and the CSF to
plasma ratio of HIV RNA was higher later in the dosing interval of 8 hours.
That is because the plasma indinavir levels decline towards 8 hours but the
CSF indinavir level remains the same.

Data from two groups of individuals were reported. In group A, 9/10 individuals
had <200 copies/ml CSF HIV RNA. Only 4/10 had plasma HIV RNA <200 copies/ml.
These 10 individuals were taking indinavir plus two nucleosides. No baseline
measure of CSF HIV RNA were done.

In group B, 9 individuals had CSF and plasma viral load measures at baseline
and week 8. At baseline, 0/9 were <200 copies/ml in plasma and 2/9 were <200
copies/ml in CSF viral load. At week 8, 1/9 was <200 copies/ml in plasma
and 6/8 were <200 copies/ml in CSF viral load.

Collier said this was an initial observational pilot study. The results are
preliminary as are the results from the ritonavir+saquinavir study.

Indinavir Twice-A-Day Dosing Study

Dr Bach-Yen Nguyen of Merck Research Labs reported the results of a preliminary
pilot study exploring dosing indinavir every 12 hours compared to the standard
dosing of every 8 hours. The objective is to see if indinavir can be successfully
dosed every 12 hours to make it a more convenient regimen for individuals. Three
arms were compared: indinavir 800 mg every 8 hrs, indinavir 1000 mg every 12
hours and indinavir 1200 mg every 12 hours. AZT+3TC was taken with indinavir
in each arm. This is a 36 week study. Preliminary 24 week data was reported.
Participants are 3TC and protease inhibitor naive, but can be AZT experienced.
The median baseline CD4 ranged from 264 to 294 in the 3 arms. The median baseline
viral load ranged from about 38,000 copies/ml to about 54,000 copies/ml in the
3 arms.

Nephrolithiasis--3 in the 800 tid arm; 2 in the 1000 bid arm; 5 in the 1200
bid arm.

Pts with serious adverse events: 1 in the 800 tid arm; 0 in the 1000 mg tid
arm and 4 in the 1200 mg tid arm. The investigators characterized the bid regimens
as well tolerated as the tid regimen.

Although the number of participants out to 24 weeks is small, the viral load
reductions, proportion undetectable, and the CD4 increases were about the same
in all 3 arms.

24 week median changes from baseline

CD4

HIV RNA

<500 copies

<50 copies

IDV 800mg tid+AZT/3TC

100+

-1.5 log (n=9)

40% (13)

40% (9)

IDV 1000mg bid+AZT/3TC

75

-2 log (n=15)

70% (17)

60% (13)

IDV 1200mg bid+AZT/3TC

75

-2 log (n=11)

70% (16)

70% (10)

Although you can see differences between some of the arms, the number of evaluable
participants is too small at 24 weeks to draw conclusions about comparisons
between the different arms. The best assessment, at this point, is that all
three arms appear comparable. Further research is needed to confirm these results.
Merck is planning a large study of 400-500 individuals to begin soon. Merck
is also planning a study of individuals currently taking the tid regimen of
indinavir and switching them to the bid regimen. Because the data is so preliminary,
it may be premature to use the twice daily dosing regimen.

Study 035, Indinavir+AZT/3TC- 2 Years Follow-up

Dr Roy Gulick of New York University Medical Canter reported 100 week data
for individuals taking indinavir+AZT/3TC in study #035. This study of 97 individuals
compared the triple regimen to AZT/3TC alone, and indinavir monotherapy. Participants
were 3TC and protease inhibitor naive, and AZT experienced (average 2.4 years).
80% of participants had taken other nucleosides prior to the study including
ddI, ddC or d4T. The median baseline CD4 and viral load were 144 cells and 43,190
copies/ml.

Previous results have been reported showing the superior viral load reductions,
CD4 increases and % undetectable for those taking the triple regimen. Between
24 and 52 weeks, individuals in the study receiving AZT/3TC or indinavir monotherapy
started to switch to the triple therapy.

After 100 weeks of therapy those receiving the triple therapy from the start
of the study had a % undetectable (<500 copies) of 79% (22/28); the median
CD4 increase from baseline was 230 cells; and, the median viral load reduction
was 2.12 log. About 60 to 70% achieved <50 copies/ml which continued through
100 weeks.

Those originally receiving AZT/3TC showed an initial viral load reduction which
trended back towards baseline. After adding indinavir after 6 months the viral
load remained about 1 to 1.5 log below baseline out to 100 weeks.

Those participants randomized to indinavir monotherapy achieved an initial
reduction in viral load of about 1.5 log but also started to trend back to baseline.
After adding AZT/3TC the viral load reductions appeared to remain the same out
to 100 weeks.

In both of these other groups they had only 30-40% at <50 copies through
the 100 weeks.

Very few AZT experienced individuals who merely added 3TC had undetectable
viral load after 6 months. After adding indinavir the best they achieve is 40%
at <500 copies/ml which does continue through the 100 weeks. The indinavir
monotherapy group initially achieved 40% at <500 copies ml through the first
6 months. After adding AZT/3TC the group maintained the 40%.

Five participants randomized to the triple regimen discontinued from the study
early. Two had increasing RNA during the trial and discontinued study medications.
Two required treatment for OIs. One dropped out for nausea. Larger numbers of
participants dropped out of the original indinavir monotherapy arm or the AZT/3TC
arm due to various reasons, most commonly due to rising viral load.

Ritonavir+Saquinavir Studies

A major subject of importance in today's treatment environment is how to treat
individuals who have failed a protease inhibitor. The following reports included
studies using the double protease inhibitor combination of ritonavir+saquinavir
to treat individuals for whom a protease inhibitor therapy has failed. Although,
in general, the preliminary results from the studies are mixed there is some
encouraging data. These studies fall short of using the most potent regimens
available. None of these studies include in the regimens: a NNRTI (nevirapine,
DMP-266, delavirdine), PMEA, or 1592U89. Studies including these drugs are being
planned in the ACTG and by the industry but are very slow in starting.

The studies presented here used a regimen composed of ritonavir+saquinavir
usually combined with recycled nucleosides because most individuals were extensively
pretreated with a variety of nucleosides.

G Kauffman reported data results from a small study of 58 individuals who had
relatively advanced HIV with baseline CD4 of 170 and baseline viral load of
about 100,000 copies/ml and prior drug experience. The following table will
give you a sense of their prior drug experience. 67% of study participants had
prior protease inhibitor experience, mostly with saquinavir. Resistance studies
are ongoing to analyze the effect of saquinavir resistance.

Prior Drug Experience of Study Group

n-58

All

AZT/3TC (n-18)

d4T/3TC (n-40)

pretreated w/ nukes

23%

na

na

treatment naive

10%

12%

8%

protease inh naive (exp)

33% (67%)

29%

33%

SQV exp (avg 19 wks)

50%

47%

52%

RTV exp

14%

18%

12%

IDV exp

3%

6%

3%

prot inh weeks

19

22

17

RTV/SQV dose-600/400mg bid

39%

44%

37%

400/600mg bid

61%

56%

63%

na - not available

% Undetectable (<500 copies/ml)

week 12 33% (n-56)

week 24 60% (n-51)

week 36 49% (n-35)

week 48 28% (n-19)

The initial viral load of about 5 log (100,000 copies/ml) rapidly dropped to
undetectable, but 7 patients at week 24, 13 at week 36, and 18 a week 48 stopped
treatment due to treatment failures and are not included in this analysis.

For individuals who responded well to therapy, CD4 counts increased appreciably
(from 170 to 450 cells by the end of the observation period). Adverse events
occurred frequently: 33% experienced diarrhea and 12% experienced nausea. 2
individuals experienced peripheral neuropathy due to d4T. In 1 person a rash
occurred. 17% of participants were incomplete responders and 10% were non-responders.
10% stopped study therapy due to adverse events. D4T experienced individuals
had a response rate of 34% while d4T naive persons had a response rate of 50%,
although this difference was not statistically significant.

The author concluded that good initial responses were experienced but after
7 months treatment failures occurred more frequently probably due to reduced
compliance or drug resistance developing.

Commentary. The conditions for success were not optimal in this study.
Although the overall response rate wasn't very good, 28% (n=19) did in fact
maintain a good response out to 48 weeks, which probably could have been improved
with the addition of a NNRTI and/or PMEA to the regimen. 50% of the participants
had an average prior exposure to saquinavir of 19 weeks. For a person failing
saquinavir, a better salvage therapy might include indinavir/a NNRTI/PMEA.

Ritonavir + Saquinavir for Indinavir Failures for those with Advanced HIV
abstract I-201

L Ruiz from Barcelona reported the data from this small study of 11 individuals
where the objective was to assess the efficacy of switching to ritonavir/saquinavir
at 24 weeks in persons with advanced HIV; and, to evaluate the correlation of
genotypic and phenotypic resistance to saquinavir with subsequent response.

Commentary. Although the study is small, the responses appear to me
relatively favorable.

11 individuals who failed indinavir were switched to ritonavir/saquinavir combination
therapy which included 2 nucleosides. But not all participants changed the RTIs
they were taking prior to switching from indinavir to ritonavir/saquinavir.
The 11 participants belonged to a cohort of 50 persons with an initial median
CD4 count of 50 (range: 34-81 cells). 8 persons were included in the genotypic
analysis. The dose regimen was 400 mg bid ritonavir and 600 mg bid saquinavir.

Patients had been treated with indinavir monotherapy (n=4) or indinavir in
combination with nucleosides: (n=7) ddC, AZT+3TC, AZT+ddI+3TC, AZT+ddC+3TC.

Patients were classified as responders or non-responders. Responders had >1
log reduction in viral load at 24 weeks (n=5). Non-responders did not have >1
log reduction in VL at any time point during the follow-up period (n=3).

8 patients (73%) completed the 24 week period. 3 remaining patients dropped
out. 1 developed a new AIDS event during the follow-up period and 2 dropped
out due to non-compliance. Ruiz characterized the combination of ritonavir/saquinavir
as well tolerated.

At week 24, the mean increase in CD4 was 60 cells (range: 17-248), and the
mean decrease in plasma viral load was 1.3 log.

Results. In all persons in this study, genotypic and phenotypic
baseline resistance mutations were detected. In 2 persons, classical mutations
to saquinavir were detected (L90M or G48V). 2 out of 3 non-responders had a
saquinavir mutation. Interestingly, 1 of the responders had resistance to all
3 protease inhibitors at baseline.

All responders also changed at least one RT inhibitor, d4T and/or 3TC, at start
of this study. The absence of a baseline saquinavir mutation was associated
with a good clinical and virological (viral load reduction) response.

Safety and Efficacy of Ritonavir+Saquinavir Added to AZT/3TC abstract
I-202

This was an open-label study of 16 persons who were pretreated with >9 months
with nucleosides and at least the last 3 months with AZT/3TC. They merely added
ritonavir+saquinavir at the dose of 600 mg bid ritonavir and 400 mg bid saquinavir;
they had 47 months (range 20-90) prior nucleoside experience.

56 patients received 600 mg bid saquinavir and 400 or 600 mg bid ritonavir,
with d4T (30-40 mg bid). Preliminary data of the first 9 weeks (phase 1) was
reported for this study. Only 2 patients had any prior nuke experience, all
were d4T and protease inhibitor naive.

Results. After 5 weeks the median viral load drop was 2 log,
after 9 weeks the preliminary median viral load drop was 2.7 log. There were
7 premature discontinuations before week 9: 2 due to fatigue, I person experienced
a liver toxicity, and 2 requested to be withdrawn. 49 were still receiving treatment
at week 9.

Of the 49 persons who completed phase I (9 weeks)

36/49 (73%) had >2 log reduction in viral load

33/49 (67%) had undetectable viral load

42/49 (86%) fulfilled either criteria

The median CD4 increase was 100 at week 9. CD8 cells increased from a mean
of 643 to 923.

Protease Inhibitor Blood Levels. Saquinavir blood levels were
measured in 16 patients who reached week 9.Ritonavir was within
normal limits in all 16 patients measured. In 1 patient saquinavir levels were
unchanged. In remaining 15 patients saquinavir levels were 10-100 times elevated
with a mean of 46 times elevation, and a median of 40 times elevation. All 16
patients who finished the first phase were responders.

Safety and Tolerability (n-16). No adverse events (A/E) related
to study medications were seen. 6 patients had 11 A/Es rated moderate to severe:
1 was unrelated to medications; 2 A/Es led to 2 premature discontinuations and
to one dose adjustment.

There were no relevant mutations at baseline--at positions 48, 90 or 82. The
authors concluded that a very nice full response to therapy was seen in the
initial phase of this study: 79% by intent to treat and 86% by those actually
completing first 9 weeks (7 premature discontinuations). Saquinavir given in
a dose of 400 to 600 mg bid in combination with 400 mg bid ritonavir in combination
with d4T was well tolerated in the majority of patients.

Experience with a Ritonavir+Saquinavir Based Regimen for the Treatment of
HIV Infection in Subjects Developing Increased Viral Loads While Receiving Nelfinavir
abstract -204

This report was well anticipated and discussed before, during and after the
presentation. As you know there is much concern about cross-resistance between
protease inhibitors. The concern is as follows: if you fail one and have resistance
your ability to benefit from subsequent protease inhibitor therapy could be
little or none. Research is ongoing to explore a variety of different potent
regimens that could be effective for an individual after developing resistance
to a protease inhibitor.

Some of the different drugs that are or will be explored in the near future
in different combinatorial arrangements include: ritonavir+saquinavir, nelfinavir+saquinavir,
indinavir+nevirapine, indinavir+delavirdine,141W94+indinavir, 141W94+nelfinavir,
PMEA, 1592U89, DMP-266, nevirapine, delavirdine, ABT-378. All of these drugs
are reviewed the July issue of our newsletter, NATAP Reports, which is
on our web site.

The regimen that may work for any given individual may vary according to their
history of antiretroviral use. As with all treatment regimens, they need to
be tailored to the individual's needs and experiences.

Prior to the St. Petersburg International Workshop on Resistance this June
1997, many predicted and were concerned about cross-resistance between protease
inhibitors. At the workshop studies were presented which reinforced these concerns
and the likelihood of cross-resistance. However, researchers are designing potent
multi-drug combinations which will include new drugs. As I mentioned above,
studies will explore the possibility that protease resistant virus can be suppressed
by these regimens.

"One of the important questions not resolved at the workshop in St. Petersburg
is whether the risk for development of cross-resistance to other protease inhibitors
is lower when nelfinavir is used first", Joep Lange and Douglas Richman,
Antiviral Therapy, Vol 2, Number 3. We need hard data from well designed studies
to answer that unresolved question.

However, this study is a first step in addressing the question. The study took
individuals who failed nelfinavir therapy in 3 different nelfinavir studies
(506, 511 and 525). They were treated with ritonavir+saquinavir+d4T+3TC. Keith
Henry, the author, cautioned that the data resulting so far is preliminary (follow-up
to 16 weeks), the key is the durability of the results; and, the participants
did not switch over early or immediately after first failing nelfinavir. Some
researchers suspect that if you can detect a viral load rebound immediately
after its occurrence; and if you make adequate therapy changes, you may be able
to durably suppress viral load. All the patients, in this study, had high viral
loads immediately prior to initiating the ritonavir/saquinavir regimen.

Additionally, all the participants had an average time of pretreatment with
3 or 4 nucleosides of 1.8 years. They all had prior experience with d4T and
3TC; and in a sampling of 16 persons for genotypic mutations 7/11 had 3TC resistance
prior to receiving the switch over 4-drug regimen. The study results may have
been further improved by using drugs in combination with ritonavir/saquinavor
which the patients had never seen like PMEA, or a NNRTI.

19 patients who failed nelfinavir as participants in one of three nelfinavir
studies (studies 506, 511, and 525) were participants in this study. 11 were
participants in 506, 1 from 511, and 7 from 525. All participants received ritonavir+saquinavir
(400 mg bid of both)+3TC 150 mg bid+d4T 40 mg bid.

Participants in 506 received nelfinavir+d4T. Their prior RTI experience included:
AZT, 3TC, ddI, ddC, delavirdine. 5 participants from 506 and 1 from 511 had
not previously taken 3TC. Participants in 511 received nelfinavir+AZT+3TC, but
were treatment-naive, they had no prior drug experience. Henry reported that
the 525 participants had extensive prior nucleoside experience. The study design
for 525 was nucleoside experienced individuals (AZT, 3TC, d4T, ddI, ddC) randomized
to either add nelfinavir to their existing nucleoside regimen or to switch nucleosides
and add nelfinavir.

The baseline characteristics as reported by Henry

506/511

525

mean HIV RNA prior to NFV (bDNA)

130,646 (14,670-499,600)

263,027 (9681-1,600,000)

mean CD4 prior to NFV

208 (63-463)

65 (<10-135)

mean prior NFV use

41 (20-56)

30 (20-40)

mean HIV RNA prior to RTV/SQV

60,948 (1075-146,400)

233,667 (11990-1,186,000)

mean CD4 prior to RTV/SQV

226 (82-448)

109 (13-217)

mean # prior RTIs used

3

4

mean prior RTI use

1.8 (0.1-5.8)

(0.3-6.9)

numbers in parenthesis are a range

The following table shows that resistance to nelfinavir was broadly present,
by the presence of a mutation at D30N. Agouron has reported that D30N is the
mutation predominantly responsible for resistance developing to nelfinavir.
L90M is a mutation that can occur from resistance developing to saquinavir,
or in some cases from use of other protease inhibitors. I84V is a mutation that
can occur from resistance to ritonavir or indinavir. M184I/V is a mutation from
3TC resistance. This data suggests there was more broad 3TC resistance in the
25 group.

Genotypic Changes Prior to Substudy

Change

506/511

525

D30N

9/11

4/5

L90M

2/11

0/5

I84V

0/11

0/5

M184I/V (3TC)

2/6

5/5

Other RTI mutations

4/6

4/5

Data from Merck Research Labs

There was a difference in response between the participants from 506/511 and
those from 525. As you can see from the baseline characteristics, those from
525 had more advanced HIV ( higher viral load, lower CD4). For the 12 participants
in this substudy who came from 506/511, their approximate mean viral load reduction
from baseline after initiating the substudy 4-drug regimen was: -1.6 log (n-10)
at 4 weeks, -1.7 log at 8 weeks (n-11), -1.6 log at 12 weeks (n-8), and -1.4
log at 16 weeks (n-7).

12/12 (100%) of the participants from the 506/511 study were able to initially
suppress their viral load <500 copies/ml (undetectable by bDNA test). At
16 weeks, 6/7 individuals were undetectable, <500 copies/ml. Henry reported
that there is one person out to 12 months with undetectable viral load. He also
reported 2/6 had <20 copies/ml at 16 weeks. The CD4 increases were about
80 cells.

The response for the 7 individuals from the 525 study were not as encouraging.
3/7 (43%) were undetectable (<500 copies/ml) at 16 weeks. 4 persons rebounded.
1 person was non-compliant, another's viral load fell to 593 copies/ml but then
rebounded.

One person, who was non-compliant, received directly observed therapy and reduced
their viral load by 1.5 log.

Following are the positions at which genotypic changes occurred for two selected
patients (pt# 4 and pt# 1) from the 525 study group after the switch in therapy:

Experience with a Ritonavir+Saquinavir Based Regimen for the Treatment of HIV
Infection in Subjects Developing Increased Viral Loads While Receiving Nelfinavir
- abstract 204

pt #

Before Switch, After 36 wks NFV Use

After Switch, 12 wks on RTV/SQV

525-4

D30N, A71A/V

D30N, L33F/L, A71T, I84V, N88D,L90M, I72I/v

525-1

D30N, K45K/R, M46I, A71A/T, N88D

M46I, A71V, I84V, N88D, L90M

The first two 525 failures who failed RTV/SQV had suboptimal blood levels for
both drugs. 2/16 had the L90M mutation after nelfinavir failure, but both reduced
viral load to undetectable.

The author concluded (1) maintaining a high level of suppression may be a challenge
and partly due to the extent of prior RTI experience and disease stage, and
(2) nelfinavir failure was most often associated with D30N in conjunction with
M46I, A71V, and N88D.

I want to remind readers that the author, Keith Henry, cautioned listeners
that this information is preliminary. The study is small and the durability
of the benefits are the true test. Although encouraging results came from the
506/511 group, 16 weeks is not enough time to judge the durability. Follow-up
is ongoing and will be reported. Again, a more potent regimen than used in this
substudy may be more successful in durably suppressing viral load.

Fortovase- the new formulation of saquinavir

The dosing regimen for the new saquinavir (SGC) will be 1,200 mg three times
per day (tid). Based on recent studies, it's been reported that 1,200 mg tid
of saquinavir SGC has resulted in increased drug blood levels that are 10-fold
higher than that of Invirase, the older formulation of saquinavir.

Reports of data from several different studies examining the new saquinavir
were presented both at the ICAAC conference and at meetings outside the conference
in Toronto. Following is a consolidation of highlights of the data.

The SUN Study was an open-label non-comparative examination of the triple
regimen of saquinavir SGC (soft-gel capsule), Fortovase, plus AZT and 3TC. 42
treatment-naive individuals were enrolled with mean baseline and HIV RNA and
CD4 of 4.8 log (about 63,000 copies/ml) and 419 cells, respectively. The study
is ongoing and the following data is preliminary.

The investigators reported that after 20 weeks, the reduction in viral load
for 23 evaluable study participants was 3.34 log. However, the investigators
used a more sensitive viral load test (20 copies/ml), which can report (although
accuracy can be inconsistent) viral load reductions down to a lower level than
you'll get from using the 400 copy test. 91% were <400 copies/ml (undetectable),
and 60% had a viral load at <20 copies/ml. 19/42 participants had withdrawn
from the study by week 20 and were not included in the analysis: 2 due to adverse
events, 3 due to non-compliance, 4 due to refusal of treatment, 6 lost to follow-up,
1 missed week 16th visit. After 16 weeks the mean CD4 increase was 170 cells.

Safety. Investigators characterized the triple combination as
well-tolerated. The most frequent side effects related to study drug, less than
5%, was nausea, vomiting, diarrhea, and headaches. 1 person had a grade III
AST/ALT (liver function tests) at week 4 which resolved after discontinuing
study treatment. 1 person had a grade IV AST/ALT at week 12 associated with
acute hepatitis A. An approximate 20% incidence of diarrhea has been reported
associated with saquinavir SGC in a different study.

At week 8, the median reduction in viral load was to below detection with at
least about a 2 log reduction for both groups. This median change was sustained
out to 24 weeks for both groups where the n=3 for each group. At week 16 n=8
for the SQV SGC group and 7 for the indinavir group. The CD4 increases were
substantial for both groups.